A Chinese Female Morvan Patient with LGI1 and CASPR2 Antibodies

Zhang et al. BMC Neurology (2016) 16:37 DOI 10.1186/s12883-016-0555-x

CASE REPORT Open Access A Chinese female Morvan patient with LGI1 and CASPR2 antibodies: a case report Li Zhang1, Qiang Lu1*, Hong-Zhi Guan1, Jun-Hua Mei2, Hai-Tao Ren1, Ming-Sheng Liu1, Bin Peng1,3 and Li-Ying Cui1,3

Abstract Background: Morvan syndrome is a rare disorder characterized by the combination of peripheral nerve hyperexcitability, encephalopathy and dysautonomia with marked insomnia. It was reported to have association to antibodies to voltage-gated potassium channels including contactin associated protein-like 2 antibodies (CASPR2-Ab) and leucine-rich glioma inactivated protein 1 antibodies (LGI1-Ab). LGI1-Ab was reported to associate with seizures, amnesia, confusion, hyponatraemia and a good prognosis, while CASPR2-Ab with peripheral presentations, probable risk for tumor and a poor prognosis. The vast majority of Morvan syndrome patients were male, with normal magnetic resonance imaging of the brain. Case presentation: We report a female case presenting with a combination of bilateral leg pain, widespread myokymia, memory disturbance, seizure, hyperhidrosis and insomnia. She had antibodies targeting CASPR2 and LGI1, tested by the indirect immunofluorescence test, which demonstrated the diagnosis of typical Morvan syndrome as well as classical limbic encephalitis. Cranial MRI revealed bilateral hyper-intensity of the medial temporal lobe, insular lobe and basal ganglia on T2/FLAIR and DWI sequence. As the treatment carried on, her serum LGI1-Ab disappeared and her memory loss, seizure and confusion quickly relieved. But her peripheral presentations did not relieve until serum CASPR2-Ab turned negative. Intravenous immunoglobulin treatment showed limited efficacy while she achieved almost complete remission with corticosteroids therapy. Conclusions: This case provides a rare female resource of Morvan syndrome, which is the first patient with both CASPR2-Ab and LGI1-Ab positive Morvan syndrome in China and one of the few female patients with Morvan syndrome reported so far. Through the detailed analysis of her clinical course, the diverse and overlapping clinical phenotype of CASPR2-Ab and LGI1-Ab in patients with Morvan syndrome was obvious and interesting. Keywords: Morvan syndrome, Leucine-rich glioma inactivated protein 1 antibodies, Contactin associated protein-like 2 antibodies, Limbic encephalitis, Voltage-gated potassium channels

Background and muscle stiffness [2, 3]. And Morvan syndrome is a Limbic encephalitis (LE) is defined as the subacute devel- rare disorder characterized by the combination of PNH or opment of seizures, short-term memory loss, confusion NMT, encephalopathy and dysautonomia with marked and psychiatric symptoms suggesting the involvement of insomnia [4]. The vast majority of Morvan syndrome the limbic system [1]. Peripheral nerve hyperexcitability patients were male, with normal magnetic resonance (PNH) is used to describe acquired neuromyotonia imaging (MRI) of the brain [4]. Plenty of studies have (NMT) or partial manifestations of this disorder including demonstrated the association between Morvan syndrome cramps, muscle twitching (fasciculations or myokymia) and antibodies to voltage-gated potassium channels (VGKC-Ab) including contactin associated protein-like * Correspondence: [email protected] 2 antibodies (CASPR2-Ab), leucine-rich glioma inacti- 1Department of Neurology, Peking Union Medical College Hospital, Chinese vated protein 1 antibodies (LGI1-Ab) and other anti- Academy of Medical Sciences and Peking Union Medical College, – Shuaifuyuan 1, Dong Cheng District, Beijing 100730, China bodies [2, 4 8]. LGI1-Ab was reported to associate Full list of author information is available at the end of the article with seizures, amnesia, confusion, hyponatraemia and a good prognosis, while CASPR2-Ab with peripheral

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presentations, probable risk for tumor and a poor prog- 0.4 g/kg/day for 5 days and continued oral prednisolone nosis [2, 4, 9]. 20 mg/day treatment for a month. Carbamazepine 0.1 g Here we report on a both CASPR2-Ab and LGI1-Ab tid was administered instead of levetiracetam to prevent positive female patient who presented with typical Morvan epilepsy recurrence. Her memory loss and confusion syndrome as well as classical LE, which is the first patient responded quite well to the immunotherapy, while bilat- with double antibodies positive Morvan syndrome in eral leg pain, myokymia, shaking of the toes, insomnia as China and one of the few female patients with Morvan well as hyperhidrosis mildly relieved but not disap- syndrome reported so far. She had an abnormal cranial peared. Repeated CSF routine, cells, glucose, chloride, MRI, and and achieved almost complete remission with protein, CASPR2-Ab and LGI1-Ab were within the nor- the treatment of steroids and IVIG. Through the detailed mal range. Serum CASPR2-Ab was still positive (+) analysis of her clinical course, we aim to emphasis the while LGIA-Ab turned negative. Electromyography diverse and overlapping clinical phenotype of LGI1-Ab (EMG) revealed abnormal F wave in bilateral lower limb, and CASPR2-Ab in patients with Morvan syndrome. indicating abnormal peripheral nerve excitability. Nerve conduction velocity showed normal motor and sensory Case presentation nerve responses, and somatosensory evoked potential A 40-year-old Chinese woman presented with a 2-month (SEP) of lower limbs were normal. Methylprednisolone history of bilateral leg pain, widespread myokymia, mem- pulse therapy (1 g for 3 days and 500 mg for 3 days) was ory disturbance, seizure, hyperhidrosis and insomnia. Two commenced, after which all symptoms above got signifi- months prior to the admission, she developed repeating cant remission. Repeated MMSE was 27/30. Repeated pain in bilateral proximal end of lower limbs, accompan- serum CASPR2-Ab turned weakly positive (±). Prednis- ied with widespread myokymia, shaking of the toes, olone 60 mg daily oral treatment was administered sub- insomnia and hyperhidrosis. One week later, she devel- sequently with slow tapering (Fig. 3). She did a good oped seizures for three times a day, consisting of eyes on job in following the treatment plan and showed no spe- the turn, froth at the mouth, unresponsiveness and con- cific adverse reaction. In a 50 days’ follow-up, after vulsion of bilateral upper limbs. Levetiracetam was started stopping all the drugs for almost 1 week, her repeated by the referring doctor, which relieved her seizure soon. MRI (Fig. 1) were normal and all of her symptoms ex- From then on, family members noted her recent memory perienced complete remission. loss, confusion and apathy. Cranial MRI (Fig. 1) revealed bilateral hyper-intensity of the medial temporal lobe, insular lobe and basal ganglia on T2/FLAIR and DWI Methods sequence. Electroencephalography (EEG) showed a few Serum from the patient was qualitatively tested for neuro- non-specific slow waves in background and occasional ab- pil antibodies associated with autoimmune encephalitis normal sharp waves on occipital lead during wakefulness. including antibodies to glutamate receptors type NMDA, Serum test in a cell based assay showed serum VGKC- type AMPA1 and type AMPA2, LGI1, CASPR2 and complex proteins (EUROIMMUN, Germany) including GABARB1/B2using the indirect immunofluorescence test CASPR2-Ab strongly positive (+++) and LGI1-Ab posi- (IIFT) (EUROIMMUN, FA 112d-1005-1, Germany). Cell- tive (+), while cerebrospinal fluid (CSF) LGI1-Ab was based assays (CBAs) for those antibodies were performed weakly positive (±), examined by the indirect immuno- using EU90 cells (EUROIMMUN) transfected with fluorescence test (IIFT) (Fig. 2). CSF for cells, glucose, cDNAs encoding the relevant proteins. Combinations of chloride and culture were normal, while CSF protein substrates were incubated with patient serum (1:10 dilu- was mildly elevated at 0.5 g/L. Blood natrium was nor- tion) or undiluted CSF sample. In a second step, the at- mal. Thyroid function and anti-thyroid antibodies tached antibodies were stained with fluorescein-labelled including Anti-TG and Anti-TPO was negative. Tumor anti-human antibodies (EUROIMMUN) and made visible markers (CEA, AFP, CA125, CA19-9, CA15-3, SCCAg, with a fluorescence microscope. Each slide was devided NSE, Cyfra211, TPS) and paraneoplastic neuronal anti- into six areas detected for the above-mentioned six antibodies (Hu, Ri, Yo) were all negative, and body CT scan- bodies and those areas with no specific fluorescene would ning showed no malignancy. Her mini-mental state be regard as the control of positive area with specific examination (MMSE) was 21/30. Neurologic examin- fluorescence. Fluorescence intensity level was used to ation revealed only myokymia in the limbs, shaking of describe the intensity of the specific fluorescence as a the toes, and hyperhidrosis. She has no remarkable past numeric value, reaching from “0” or “−” (no specific fluor- history, personal history or family history. escence) to “5” or “+++++” (extremely strong specific VGKC-Ab related limbic encephalitis and Morvan’s fluorescence). The deviation in the fluorescence intensity syndrome were presumed diagnosis. She was treated of the IIFT amounted to no more than ± 1 fluorescence with intravenous immunoglobulin (IVIG) at a dose of intensity level for all samples. Zhang et al. BMC Neurology (2016) 16:37 Page 3 of 6

Fig. 1 Cranial MRI of our patient. Diffusion-weighted magnetic resonance imaging (DWI) (a) and the corresponding plane in fluid-attenuated inversion recovery (FLAIR) (b) showed bilateral hyper-intensity of the medial temporal lobe, insular lobe and basal ganglia (arrows). Repeated MRI were normal in February 28, 2015. (c, d)

Discussion seizures as the neuropsychiatric manifestations, but There are very few female Morvan syndrome cases more hallucinations and agitation. Whereas the presence with both CASPR2-Ab and LGI1-Ab positive [1, 7, 10]. of neuromyotonia, dysautomia (hyperhidrosis, cardiovas- Loukaides et al. [8] have reported a 67-year-old man with cular) and neuropathic pain would help to distinguish autoantibodies targeting LGI1, CASPR2 and Contactin-2/ Morvan syndrome from classical LE [4]. In addition, Tag-1 presenting with Morvan syndrome. Klein et al. [7] most Morvan syndrome patients were reported with and Lai et al. [9] have reported 9 patients whose CASPR2- normal cranial MRI findings [4, 8]. For this patient, we Ab and LGI1-Ab were both positive, but none of them would like to attribute the encephalopathic clinical fea- were diagnosed with Morvan syndrome. Although 29 Mor- tures as well as abnormal intensity on cranial MRI to van syndrome cases have been collected by Irani et al. [4], the common phenomenon of LE. Thus this patient of which only two patients were female. should be diagnosed with classical LE as well as Morvan Our patient’s symptoms can be devided into following syndrome. aspects. Neuropathic pain, widespread myokymia and There was a detailed change of the clinical manifest- shaking of the toes were manifestations of PNH [2, 3]. ation and titers of antibodies along with the treatment. And epilepsy, recent memory loss, confusion and apathy In the beginning, her serum CASPR2-Ab was strongly were classified as symptoms of limbic encephalitis (LE) positive (+++) and LGI1-Ab was positive (+), while CSF [1, 4, 9]. With hyperhidrosis as dysautonomia and LGI1-Ab was weakly positive (±). After the treatment of insomnia, the patient was diagnosised with a typical IVIG, both her serum and CSF LGI1-Ab turned nega- Morvan syndrome [4]. Compared with LE, Morvan syn- tive, and in the meanwhile her memory loss, confusion drome showed significant less amnesia, confusion or and apathy resolved to some extent. At the same time, Zhang et al. BMC Neurology (2016) 16:37 Page 4 of 6

Fig. 2 The immunoreactivity of patient’s serum to CASPR2 and LGI1 proteins. EU90 cells were transfected with cDNAs encoding CASPR2, LGI1 and other four neuropil proteins associated with autoimmune encephalitis (EUROIMMUN, FA 112d-1005-1, Germany), incubated with this patient’s serum and detected by IIFT. This patient’s serum collected at different time showed different immunoreactivity to CASPR2 (a, d, g) and LGI1 (b, e, h), and areas with no specific fluorescene to other proteins on the same slide tested at the same time would be regard as control (c, f, i). The patient’s serum collected on November 26, 2014 showed strong binding to the surface of cells expressing CASPR2 proteins (a) (50x) and moderate binding to the ones expressing LGI1 proteins (b)(50x). The patient’s serum collected on December 26, 2014 showed moderate binding to the surface of cells expressing CASPR2 proteins (d) (50x) and no binding to the ones expressing LGI1 proteins (e) (50x). The patient’s serum collected on January 12, 2015 showed weak binding to the surface of cells expressing CASPR2 proteins (g) (100x) and no binding to the ones expressing LGI1 proteins (h)(100x) her serum CASPR2-Ab kept positive, from which we LGI1-Ab and CASPR2-Ab, among which there were three could conclude that LGI1-Ab was the primarily relevant patients with additional contactin-2 antibodies. Different antibody for these encephalopathic symptoms. In this antibodies may contribute to the distinct phenotype of case we can’t arbitrarily contribute the seizure to LGI1- Morvan syndrome. Our case also corresponded with the Ab for the timely treatment with antiepileptic drugs condition that Morvan syndrome is usually associated since the beginning of seizure. After the methylpredniso- with high-titer CASPR2-Ab and often accompanied by lone pulse therapy, her symptoms of PNH, insomnia and lower-titer LGI1-Ab [4]. From her treatment and clinical hyperhidrosis almost disappeared while serum CASPR2- course, the diverse and overlapping effects of LGI1-Ab Ab turned weakly positive. Besides, titer of CASPR2-Ab and CASPR2-Ab in Morvan syndrome were apparent. was always higher than that of LGI1-Ab, which indicated Irani et al. [4] have described 29 Morvan syndrome the association of CASPR2-Ab with PNH and Morvan cases, of which 27 patients were all male. And all five syndrome. This agrees with the different clinical features Morvan syndrome patients reported by Sarosh et al. [6] of CASPR2-Ab and LGI1-Ab that CASPR2-Ab was in were male. Seven of eight patients with positive association with PNH and Morvan syndrome while CASPR2-Ab collected by Lancaster et al. [2] with or LGI1-Ab with memory loss, cognitive impairment and without Morvan syndrome were male. The striking male seizures [2, 6, 7, 9]. preponderance in patients with Morvan syndrome and The combination of LGI1-Ab and CASPR2-Ab attracted CASPR2-Ab related disease is interesting. In previous our attention. Within the 29 Morvan cases reported by study, CASPR2 mRNA has been found in the prostate Irani et al. [4], there were 15 patients with both positive tissue [11] and Morvan syndrome onset was observed Zhang et al. BMC Neurology (2016) 16:37 Page 5 of 6

Fig. 3 Timing of clinical course, antibodies test and treatment. 0, No symptom; +, mild; ++, moderate; +++, severe; IVIG, intravenous immunogloblin; PED, prednisone; MP, methylprednisolone; LEV, Levetiracetam; CBZ, carbamazepine after scrotal drainage in some cases [4]. These might in- However, some other studies showed no neoplasm in a dicated that the storage and release of relevant anti- long follow-up in CASPR2-Ab positive patients [2, 9]. bodies in the male productive system increase the titer And there has been no evidence showing the difference of serum antibodies to cause Morvan syndrome [4, 11]. of neoplasm concurrent rate between both CASPR2-Ab In the contrast, this case would add a valuable female re- and LGI1-Ab positive patients and only CASPR2-Ab source to the mechanism study of Morvan syndrome positive patients [4, 7]. With a short term follow-up, and VGKC antibodies. there has been no finding showed any neoplasm in this Although LGI1-Ab was commonly agreed with no as- patient. sociation with neoplasm, no agreement on the relation Most Morvan syndrome patients without neoplasm between CASPR2-Ab and neoplasm has been reached. responded well to immunotherapy including IVIG, Previous studies have shown CASPR2-Ab positive plasma exchange and corticosteroids, while patients who patients were more likely to be found with neoplasm coexist with neoplasm mostly had a poor treatment out- especially thymomas, accompanied with acetylcholine come or prognosis [2, 4, 6]. In this case report, as for receptor antibodies and myasthenia gravis (MG) [4, 6, clinical syndromes, the patient got limited benefit from 11–13]. And CASPR2 has been reported to function as a the initial IVIG treatment while got significant improve- tumor suppressor gene in glioma by Bralten et al. [14]. ment with methylprednisolone pulse therapy, which was Zhang et al. BMC Neurology (2016) 16:37 Page 6 of 6

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Acknowledgments We thank the physicians who provided clinical support and clinical Submit your next manuscript to BioMed Central examination. And we also wish to thank our patient and her family. and we will help you at every step: Author details 1Department of Neurology, Peking Union Medical College Hospital, Chinese • We accept pre-submission inquiries Academy of Medical Sciences and Peking Union Medical College, • Our selector tool helps you to ﬁnd the most relevant journal Shuaifuyuan 1, Dong Cheng District, Beijing 100730, China. 2Department of • We provide round the clock customer support Neurology, Wuhan First Hospital, Hospital of Integrated Traditional and Western Medicine, Tongji Medical College of Huazhong University of Science • Convenient online submission 3 and Technology, Wuhan 430022Hubei Province, China. Neuroscience • Thorough peer review Center, Chinese Academy of Medical Sciences and Peking Union Medical • Inclusion in PubMed and all major indexing services College, Shuaifuyuan 1, Dong Cheng District, Beijing 100730, China. • Maximum visibility for your research Received: 3 November 2015 Accepted: 1 March 2016 Submit your manuscript at www.biomedcentral.com/submit